Pancreatic adenocarcinoma is the fourth most common cause of cancer death in the developed world. Less than 10% of patients survive for more than 1 year following diagnosis and the 5-year survival rate (1-3%) is the lowest of any cancer. Despite the advance in the research of pancreatic cancer, patients with this devastating disease have a very poor prognosis. Current chemotherapy, radiation therapy, and surgical procedures are largely ineffective in the treatment of this disease because most pancreatic cancers have already progressed into locally advanced unresectable or metastatic disease at the time of diagnosis. The goal of this proposal is to identify markers for detecting pancreatic cancer at an early stage by using a simple non-invasive screening test. When pancreatic cancer has not reached to advance, unresectable or metastatic stages, survival of patients with pancreatic cancer can be improved by using therapeutic approaches such as pancreaticoduodenectomy plus chemoradiation. The most promising approach for the early diagnosis of cancer utilizes tumor markers. However, tumor marker with both high sensitivity and high specificity, especially for screening and diagnosis of early stages of pancreatic cancer remains to be found. By using different approaches for screening differentially expressed genes between the normal and pancreatic tumor and between nonmetastatic and metastatic pancreatic tumor cell lines, overexpression of gamma synuclein and tropomyosin-related kinase B (TrkB) was identified. High levels of gamma synuclein can be found by immunoblotting in 38% (21 of 56) of blood samples from pancreatic cancer patients, but not in normal controls. Overexpression of TrkB was found in metastatic human pancreatic cancer cells and correlated with liver metastasis in pancreatic cancer patients. In the proposed study, we will determine whether gamma synuclein is a potential tumor marker for early detection of pancreatic cancer by developing more sensitive assays such as ELISA for analyzing blood samples from normal controls and patients with pancreatic cancer and other type of cancers as well as sera from benign diseases such as pancreatitis and hepatitis. We will examine the expression of y-synuclein in PanlN stages. We will determine whether TrkB is a potential prognostic marker for pancreatic cancer metastasis by correlating the levels of TrkB immunostaings from surgical specimens and endoscopic retrograde cholangiopancreatography (ERCP) samples with the various stages of pancreatic cancer. Our proposed experimental approaches represent the required verification step in identification of tumor marker for diagnosis and prognosis regardless of the techniques used in the initial screening. Our study may identify the tumor markers for developing an early detection method for screening of asymptomatic cases to detect pancreatic cancer at an early, localized, and curable stage. Our results may also provide a prognostic marker for metastasis of pancreatic cancer and a direction for the rational treatment of patients with pancreatic cancer, and the future clinical studies required to extend the survival of these patients. [unreadable] [unreadable] [unreadable]